Regulatory T cells are well known for their role in dampening the immune responses to self-antigens and thereby helping to prevent autoimmune disease. Additionally, recent work has highlighted the importance of regulatory T cells in immunity to infectious disease. Thus, the question arises as to how regulatory T cells can participate in both of these goals so important to human survival - preventing damaging immune responses to self while simultaneously permitting immune responses to be generated to fight foreign infectious agents. Previous studies have pointed to a role for regulatory T cells in limiting late immune responses to various infectious agents, thereby minimizing immune response-induced tissue damage while preventing or diminishing pathogen clearance. However, we recently demonstrated a novel and unexpected role for regulatory T cells in facilitating early immune responses to genital herpes simplex-2 (HSV-2) infection by orchestrating a timely trafficking of immune effector cells to the site of infection where they can fight infection. Therefore, this unexpected finding of an immune response-promoting function of regulatory T cells has subsequently led to several new lines of work that will be addressed in this proposal. Specifically, we will first address the role of regulatory T cells during the immune response to primary challenge with genital HSV-2 infection and compare this role to that during a second common mucosal infection that is considered to be a major public health threat- influenza virus infection. We hypothesize that the role of Tregs can vary depending on the type of pathogen, the location of the cells, the timing of infection, and the route of infection, and so we expect that these two viral systems will provide a unique opportunity to compare and contrast the role of Tregs during different types of infections that infect different mucosal surfaces. Secondly, following up on work from our previous studies, we will characterize the mechanisms by which regulatory T cells modulate dendritic cell function during mucosal viral infections. Finally, we will determine if regulatory T cells must be antigen-specific in order to respond to genital HSV-2 infection. Results from these studies will help to reveal the roles of regulatory T cells during various types of mucosal viral infections at different mucosal surfaces of the body, as well as the different roles that regulatory T cells could play at various phases of the immune response to viruses. We expect that knowledge gained from this research program will assist in the generation of improved clinical interventions for mucosal viral infections, including vaccines. Our previously published work as well as preliminary data presented in this proposal suggests that regulatory T cells play several important roles in the immune response to viruses; thus, gaining an understanding of exactly what these cells do as well as where and when in the course of an immune response is vital for designing future vaccines that will allow regulatory T cells to effectively assist in generating and maintaining protective immune responses. PUBLIC HEALTH RELEVANCE: Mucosal viral infections such as herpes and influenza pose a public health threat in the United States and worldwide. A role for regulatory T cells, which are potent negative regulators of the adaptive and innate immune responses, is poorly understood in the case of viral infection in general and in the cases of mucosal infections in particular. As mucosal exposure is the route via which the general population encounters the majority of common viruses that impact public health, the goal of this proposed research program is to better understand how regulatory T cells modulate immunity to mucosal viral infections. The proposed studies will assist in understanding the role that regulatory T cells play in HSV and influenza viral infections and disease progression, an important step in advancing the overall goal of finding new therapeutic targets for vaccines and treatments to combat mucosal viral infections.